Table 4. Efficacy of ARIXTRA Injection in the Prophylaxis of Thromboembolic Events Following Knee Replacement Surgery

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1 Table 4. Efficacy of ARIXTRA Injection in the Prophylaxis of Thromboembolic Events Following Knee Replacement Surgery Endpoint Fondaparinux Sodium 2.5 mg SC 1 Enoxaparin Sodium 30 mg SC every 12 hours 2 All Treated Knee Replacement Surgery Patients N = 517 N = 517 All Evaluable 3 Knee Replacement Surgery Patients VTE 4 45/ % 5 (9.2, 16.3) 6 101/ % (23.3, 32.7) All DVT 45/ % 5 (9.2, 16.3) 98/ % (22.6, 32.0) Proximal DVT 9/ % 7 (1.1, 4.6) 20/ % (3.3, 8.2) Symptomatic PE 1/ % 7 (0.0, 1.1) 4/ % (0.2, 2.0) 1 Patients randomized to ARIXTRA 2.5 mg received the first injection 6 ± 2 hours after surgery providing that hemostasis had been achieved. 2 Patients randomized to enoxaparin sodium received the first injection at 21 ± 2 hours after surgery closure providing that hemostasis had been achieved. 3 Evaluable patients were those who were treated and underwent the appropriate surgery (i.e. knee replacement surgery), with an adequate efficacy assessment up to Day VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day p value < Numbers in parentheses indicates 95% confidence interval. 7 p value: NS. Prophylaxis of Thromboembolic Events Following Abdominal Surgery in Patients at Risk for Thromboembolic Complications: Abdominal surgery patients at risk included the following: Those undergoing surgery under general anesthesia lasting longer than 45 minutes who are older than 60 years with or without additional risk factors; and those undergoing surgery under general anesthesia lasting longer than 45 minutes who are older than 40 years with additional risk factors. Risk factors included neoplastic disease, obesity, chronic obstructive 11

2 pulmonary disease, inflammatory bowel disease, history of deep vein thrombosis (DVT) or pulmonary embolism (PE), or congestive heart failure. In a randomized, double-blind, clinical trial in patients undergoing abdominal surgery, ARIXTRA 2.5 mg SC started postoperatively was compared to dalteparin sodium 5,000 IU SC, with one 2,500 IU SC preoperative injection and a 2,500 IU SC first postoperative injection. A total of 2,927 patients were randomized and 2,858 were treated. Patients ranged in age from 17 to 93 years (mean age 65 years) with 55% men and 45% women. Patients were 97% Caucasian, 1% black, 1% Asian, and 1% others. Patients with serum creatinine level more than 2 mg/dl (180 µmol/l), or platelet count less than 100,000/mm 3 were excluded from the trial. Sixty-nine percent (69%) of study patients underwent cancer-related abdominal surgery. Study treatment was continued for 7 ± 2 days. The efficacy data are provided in Table 5 below and demonstrate that prophylaxis with fondaparinux sodium was associated with a VTE rate of 4.6% compared with a VTE rate of 6.1% for dalteparin sodium (p = NS). 12

3 Table 5. Efficacy of ARIXTRA Injection In Prophylaxis of Thromboembolic Events Following Abdominal Surgery Endpoint Fondaparinux Sodium 2.5 mg SC Dalteparin Sodium 5,000 IU SC All Treated Abdominal Surgery Patients N = 1,433 N = 1,425 All Evaluable 1 Abdominal Surgery Patients VTE 2 47/1, % 3 (3.4, 6.0) 4 62/1, % (4.7, 7.7) All DVT 43/1, % (3.1, 5.6) Proximal DVT 5/1, % (0.2, 1.1) Symptomatic VTE 6/1, % (0.2, 0.9) 59/1, % (4.4, 7.4) 5/1, % (0.2, 1.1) 5/1, % (0.1, 0.8) 1 Evaluable patients were those who were randomized and had an adequate efficacy assessment up to Day 10; non-treated patients and patients who did not undergo surgery did not get a VTE assessment. 2 VTE was a composite of venogram positive DVT, symptomatic DVT, non-fatal PE and/or fatal PE reported up to Day p value versus dalteparin sodium: NS. 4 Numbers in parentheses indicate 95% confidence interval. Treatment of Deep Vein Thrombosis: In a randomized, double-blind, clinical trial in patients with a confirmed diagnosis of acute symptomatic DVT without PE, ARIXTRA 5 mg (body weight <50 kg), 7.5 mg (body weight kg), or 10 mg (body weight >100 kg) SC (ARIXTRA treatment regimen) was compared to enoxaparin sodium 1 mg/kg SC every 12 hours. Almost all patients started study treatment in hospital. Approximately 30% of patients in both groups were discharged home from the hospital while receiving study treatment. A total of 2,205 patients were randomized and 2,192 were treated. Patients ranged in age from years (mean age 61 years) with 53% men and 47% women. Patients were 97% Caucasian, 2% black, and 1% other races. Patients with serum creatinine level more than 2 mg/dl (180 µmol/l), or platelet count less than 100,000/mm 3 were excluded from the trial. For both groups, treatment continued for at least 5 days with a treatment duration range of 7 ± 2 days, and 13

4 both treatment groups received Vitamin K antagonist therapy initiated within 72 hours after the first study drug administration and continued for 90 ± 7 days, with regular dose adjustments to achieve an INR of 2-3. The primary efficacy endpoint was confirmed, symptomatic, recurrent VTE reported up to Day 97. The efficacy data are provided in Table 6 below. Table 6. Efficacy of ARIXTRA Injection in the Treatment of Deep Vein Thrombosis Fondaparinux Sodium 1 Endpoint 5, 7.5, or 10 mg SC (Treatment Regimen) Enoxaparin Sodium 1 1 mg/kg SC q 12h All Randomized N = 1,098 N = 1,107 DVT Patients Total VTE % (2.8, 5.2) % (3.0, 5.4) DVT only % (1.0, 2.6) % (1.7, 3.6) Non-fatal PE % (1.1, 2.8) Fatal PE 5 0.5% (0.1, 1.1) % (0.6, 1.9) 5 0.5% (0.1, 1.1) 1 Patients were also treated with Vitamin K antagonists initiated within 72 hours after the first study drug administration. 2 VTE was a composite of symptomatic recurrent non fatal VTE or fatal PE reported up to Day The 95% confidence interval for the treatment difference for total VTE was: (-1.8% to 1.5%). 4 Number in parentheses indicates 95% confidence interval. During the initial treatment period, 18 (1.6%) of patients treated with fondaparinux sodium and 10 (0.9%) of patients treated with enoxaparin sodium had a VTE endpoint (95% CI for the treatment difference [fondaparinux sodium-enoxaparin sodium] for VTE rates: -0.2%; 1.7%). Treatment of Pulmonary Embolism: In a randomized, open-label, clinical trial in patients with a confirmed diagnosis of acute symptomatic PE, with or without DVT, ARIXTRA 5 mg (body weight <50 kg), 7.5 mg (body weight kg), or 10 mg (body weight >100 kg) SC (ARIXTRA treatment regimen) was compared to heparin IV bolus (5,000 USP units) followed by a continuous IV infusion adjusted to maintain times aptt control value. Patients with a PE requiring thrombolysis or surgical thrombectomy were excluded from the trial. All patients started study treatment in hospital. Approximately 15% of patients were discharged 14

5 home from the hospital while receiving fondaparinux therapy. A total of 2,213 patients were randomized and 2,184 were treated. Patients ranged in age from years (mean age 62 years) with 44% men and 56% women. Patients were 94% Caucasian, 5% black and 1% other races. Patients with serum creatinine level more than 2 mg/dl (180 µmol/l), or platelet count less than 100,000/mm 3 were excluded from the trial. For both groups, treatment continued for at least 5 days with a treatment duration range 7 ± 2 days, and both treatment groups received Vitamin K antagonist therapy initiated within 72 hours after the first study drug administration and continued for 90 ± 7 days, with regular dose adjustments to achieve an INR of 2-3. The primary efficacy endpoint was confirmed, symptomatic, recurrent VTE reported up to Day 97. The efficacy data are provided in Table 7 below. Table 7. Efficacy of ARIXTRA Injection in the Treatment of Pulmonary Embolism Fondaparinux Sodium 1 Endpoint 5, 7.5, or 10 mg SC 1 (Treatment Regimen) Heparin 1 aptt adjusted IV All Randomized PE Patients N = 1,103 N = 1,110 Total VTE % (2.8, 5.1) % (3.8, 6.5) DVT only % (0.6, 1.9) Non-fatal PE % (0.7, 2.1) Fatal PE % (0.8, 2.3) % (0.9, 2.4) % (1.4, 3.2) % (0.8, 2.2) 1 Patients were also treated with Vitamin K antagonists initiated within 72 hours after the first study drug administration. 2 VTE was a composite of symptomatic recurrent non fatal VTE or fatal PE reported up to Day The 95% confidence interval for the treatment difference for total VTE was: (-3.0% to 0.5%). 4 Number in parentheses indicates 95% confidence interval. During the initial treatment period, 12 (1.1%) of patients treated with fondaparinux sodium and 19 (1.7%) of patients treated with heparin had a VTE endpoint (95% CI for the treatment difference [fondaparinux sodium-heparin] for VTE rates: -1.6%; 0.4%). 15

6 INDICATIONS AND USAGE ARIXTRA Injection is indicated for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism: in patients undergoing hip fracture surgery, including extended prophylaxis; in patients undergoing hip replacement surgery; in patients undergoing knee replacement surgery; in patients undergoing abdominal surgery who are at risk for thromboembolic complications. ARIXTRA Injection is indicated for: the treatment of acute deep vein thrombosis when administered in conjunction with warfarin sodium, and the treatment of acute pulmonary embolism when administered in conjunction with warfarin sodium when initial therapy is administered in the hospital. (See DOSAGE AND ADMINISTRATION section for appropriate dosage regimen.) CONTRAINDICATIONS ARIXTRA Injection is contraindicated in patients with severe renal impairment (creatinine clearance <30 ml/min). ARIXTRA is eliminated primarily by the kidneys, and such patients are at increased risk for major bleeding episodes (see WARNINGS: Renal Impairment). ARIXTRA prophylactic therapy is contraindicated in patients with body weight <50 kg undergoing hip fracture, hip replacement or knee replacement surgery, and abdominal surgery. During the randomized clinical trials of prophylaxis in the peri-operative period following hip fracture, hip replacement, or knee replacement surgery, occurrence of major bleeding was doubled in patients with a body weight <50 kg compared with those with a body weight 50 kg (5.4% versus 2.1%). In the clinical trial in patients undergoing abdominal surgery, the major bleeding rate was also higher in patients with a body weight <50 kg as compared to those with a body weight 50 kg (5.3% versus 3.3%), respectively. The use of ARIXTRA is contraindicated in patients with active major bleeding, bacterial endocarditis, in patients with thrombocytopenia associated with a positive in vitro test for antiplatelet antibody in the presence of fondaparinux sodium, or in patients with known hypersensitivity to fondaparinux sodium. WARNINGS ARIXTRA Injection is not intended for intramuscular administration. ARIXTRA cannot be used interchangeably (unit for unit) with heparin, low molecular weight heparins or heparinoids, as they differ in manufacturing process, anti-xa and anti-iia activity, units, and dosage. Each of these medicines has its own instructions for use. Renal Impairment (See also CONTRAINDICATIONS): Hip Fracture, Hip Replacement and Knee Replacement Surgeries: Major bleeding in patients receiving prophylactic therapy in hip fracture, hip replacement, or knee replacement surgery occurred in 1.6% (25/1,565) of patients with normal renal function, in 2.4% (31/1,288) with mild renal 16

7 impairment, in 3.8% (19/504) with moderate renal impairment, and in 4.8% (4/83) with severe renal impairment. When ARIXTRA was used according to the recommended timing of the first injection (6 to 8 hours after surgery), major bleeding occurred in 1.8% (16/905) of patients with normal renal function, in 2.2% (15/675) with mild renal impairment, in 2.3% (6/265) with moderate renal impairment, and in 0% (0/40) with severe renal impairment. Abdominal Surgery: Major bleeding in patients receiving prophylactic therapy in abdominal surgery occurred in 2.1% (13/606) of patients with normal renal function, in 3.6% (22/613) with mild renal impairment, in 6.7% (12/179) with moderate renal impairment, and in 7.1% (1/14) with severe renal impairment. When ARIXTRA was used according to the recommended timing of the first injection (6 to 8 hours after surgery), major bleeding occurred in 2.1% (10/467) of patients with normal renal function, in 3.3% (16/481) with mild renal impairment, in 5.8% (8/137) with moderate renal impairment, and in 7.7% (1/13) with severe renal impairment. Treatment of Deep Vein Thrombosis and Pulmonary Embolism: Major bleeding in patients receiving treatment for DVT and PE occurred in 0.4% (4/1,132) of patients with normal renal function, in 1.6% (12/733) with mild renal impairment, in 2.2% (7/318) with moderate renal impairment, and in 7.3% (4/55) with severe renal impairment. ARIXTRA should be used with caution in patients with moderate renal impairment (creatinine clearance ml/min). (See CLINICAL PHARMACOLOGY: Special Populations, Renal Impairment.) Renal function should be assessed periodically in patients receiving ARIXTRA. The drug should be discontinued immediately in patients who develop severe renal impairment while on therapy. After discontinuation of ARIXTRA, its anticoagulant effects may persist for 2-4 days in patients with normal renal function (i.e., at least 3-5 half-lives). The anticoagulant effects of ARIXTRA may persist even longer in patients with renal impairment (see CLINICAL PHARMACOLOGY). Hemorrhage: ARIXTRA Injection, like other anticoagulants, should be used with extreme caution in conditions with increased risk of hemorrhage, such as congenital or acquired bleeding disorders, active ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors. Laboratory Testing: Because routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aptt) are relatively insensitive measures of the activity of ARIXTRA and international standards of heparin or LMWH are not calibrators to measure anti-factor Xa activity of ARIXTRA, if during therapy with ARIXTRA, unexpected changes in coagulation parameters or major bleeding occurs, ARIXTRA should be discontinued (see PRECAUTIONS: Laboratory Tests). Neuraxial Anesthesia and Post-operative Indwelling Epidural Catheter Use: Spinal or epidural hematomas, which may result in long-term or permanent paralysis, can occur with the use of anticoagulants and neuraxial (spinal/epidural) anesthesia or spinal puncture. The risk of 17

8 these events may be higher with post-operative use of indwelling epidural catheters or concomitant use of other drugs affecting hemostasis such as NSAIDs (see Boxed Warning for Spinal/Epidural Hematomas). In spontaneous post-marketing reports, there have been several cases of epidural or spinal hematoma that have occurred in association with the use of ARIXTRA by SC injection. Thrombocytopenia: Thrombocytopenia can occur with the administration of ARIXTRA. Moderate thrombocytopenia (platelet counts between 100,000/mm 3 and 50,000/mm 3 ) occurred at a rate of 3.0% in patients given ARIXTRA 2.5 mg in the peri-operative hip fracture, hip replacement or knee replacement surgery, and abdominal surgery clinical trials. Severe thrombocytopenia (platelet counts less than 50,000/mm 3 ) occurred at a rate of 0.2% in patients given ARIXTRA 2.5 mg in these clinical trials. During extended prophylaxis, no cases of moderate or severe thrombocytopenia were reported. Moderate thrombocytopenia occurred at a rate of 0.5% in patients given the ARIXTRA treatment regimen in the DVT and PE treatment clinical trials. Severe thrombocytopenia occurred at a rate of 0.04% in patients given the ARIXTRA treatment regimen in the DVT and PE treatment clinical trials. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm 3, ARIXTRA should be discontinued. PRECAUTIONS General: ARIXTRA Injection should be administered according to the recommended regimen, especially with respect to the timing of the first dose after surgery. In the hip fracture, hip replacement, knee replacement, or abdominal surgery clinical studies, the administration of ARIXTRA before 6 hours after surgery has been associated with an increased risk of major bleeding (see ADVERSE REACTIONS: Hemorrhage and DOSAGE AND ADMINISTRATION). ARIXTRA Injection should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension, or a history of recent gastrointestinal ulceration, diabetic retinopathy, and hemorrhage. ARIXTRA Injection should be used with caution in elderly patients (see PRECAUTIONS: Geriatric Use). ARIXTRA should be used with caution in patients with a low body weight (<50 kg) for the treatment of PE and DVT. ARIXTRA Injection should not be mixed with other injections or infusions. If thrombotic events occur despite prophylaxis with ARIXTRA, appropriate therapy should be initiated. Laboratory Tests: Periodic routine complete blood counts (including platelet count), serum creatinine level, and stool occult blood tests are recommended during the course of treatment with ARIXTRA Injection. 18

9 When administered at the recommended doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aptt) are relatively insensitive measures of ARIXTRA activity, and are therefore, unsuitable for monitoring. The anti-factor Xa activity of fondaparinux sodium can be measured by anti-xa assay using the appropriate calibrator (fondaparinux). Since the international standards of heparin or LMWH are not appropriate calibrators, the activity of fondaparinux sodium is expressed in milligrams (mg) of the fondaparinux and cannot be compared with activities of heparin or low molecular weight heparins (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Pharmacokinetics and WARNINGS: Laboratory Testing). Drug Interactions: In clinical studies performed with ARIXTRA, the concomitant use of oral anticoagulants (warfarin), platelet inhibitors (acetylsalicylic acid), NSAIDs (piroxicam), and digoxin did not significantly affect the pharmacokinetics/pharmacodynamics of fondaparinux sodium. In addition, ARIXTRA neither influenced the pharmacodynamics of warfarin, acetylsalicylic acid, piroxicam, and digoxin, nor the pharmacokinetics of digoxin at steady state. Agents that may enhance the risk of hemorrhage should be discontinued prior to initiation of therapy with ARIXTRA. If co-administration is essential, close monitoring may be appropriate. In an in vitro study in human liver microsomes, inhibition of CYP2A6 hydroxylation of coumarin by fondaparinux (200 µm i.e., 350 mg/l) was 17-28%. Inhibition of the other isozymes evaluated (CYPs 2A1, 2C9, 2C19, 2D6, 3A4, and 3E1) was 0-16%. Since fondaparinux does not markedly inhibit CYP450s (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4) in vitro, fondaparinux sodium is not expected to significantly interact with other drugs in vivo by inhibition of metabolism mediated by these isozymes. Since fondaparinux sodium does not bind significantly to plasma proteins other than ATIII, no drug interactions by protein-binding displacement are expected. Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term studies in animals have been performed to evaluate the carcinogenic potential of fondaparinux sodium. Fondaparinux sodium was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK +/- ) forward mutation test, the human lymphocyte chromosome aberration test, the rat hepatocyte unscheduled DNA synthesis (UDS) test, or the rat micronucleus test. At subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area), fondaparinux sodium was found to have no effect on fertility and reproductive performance of male and female rats. Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in pregnant rats at subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area) and pregnant rabbits at subcutaneous doses up to 10 mg/kg/day (about 65 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to fondaparinux sodium. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 19

10 Nursing Mothers: Fondaparinux sodium was found to be excreted in the milk of lactating rats. However, it is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when fondaparinux sodium is administered to a nursing mother. Pediatric Use: Safety and effectiveness of ARIXTRA in pediatric patients have not been established. Geriatric Use: ARIXTRA should be used with caution in elderly patients. Over 3,000 patients, 65 years and older, have received ARIXTRA 2.5 mg in randomized clinical trials. Over 1,200 patients, 65 years and older, have received the ARIXTRA treatment regimen in the DVT and PE treatment clinical trials. The efficacy of ARIXTRA in the elderly (equal to or older than 65 years) was similar to that seen in younger patients (younger than 65 years). In the perioperative hip fracture, hip replacement, or knee replacement surgery clinical trials with patients receiving ARIXTRA 2.5 mg, the risk of major bleeding associated with use of ARIXTRA increased with age: 1.8% (23/1,253) in patients <65 years, 2.2% (24/1,111) in those years, and 2.7% (33/1,227) in those 75 years. Serious adverse events increased with age for patients receiving ARIXTRA. In patients undergoing 3 weeks of extended prophylaxis following one week of peri-operative prophylaxis after hip fracture surgery, the incidence of major bleeding was: 1.9% (1/52) in patients <65 years, 1.4% (1/71) in those years, and 2.9% (6/204) in those 75 years. In the abdominal surgery clinical trial, the risk of major bleeding associated with use of ARIXTRA increased with age: 3.0% (19/644) in patients < 65 years, 3.2% (16/507) in those years, and 5.0% (14/282) in those 75 years. In the DVT and PE treatment clinical trials with patients receiving the ARIXTRA treatment regimen, the risk of major bleeding associated with ARIXTRA increased with age: 0.6% (7/1151) in patients <65 years, 1.6% (9/560) in those years, and 2.1% (12/583) in those 75 years. Careful attention to dosing directions and concomitant medications (especially anti-platelet medication) is advised (see CLINICAL PHARMACOLOGY and PRECAUTIONS: General). Fondaparinux sodium is substantially excreted by the kidney, and the risk of toxic reactions to ARIXTRA may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function (see CONTRAINDICATIONS and WARNINGS: Renal Impairment). ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying possible adverse events and for approximating rates. The data described below reflect exposure in 8,877 patients randomized to ARIXTRA Injection in controlled trials of hip fracture, hip replacement, major knee, or abdominal surgeries, and DVT and PE treatment. Patients received ARIXTRA primarily in 2 large peri-operative 20

11 dose-response trials (n = 989), 4 active-controlled peri-operative trials with enoxaparin sodium (n = 3,616), and an extended prophylaxis trial (n = 327), an active-controlled trial with dalteparin sodium (n = 1,425), a dose-response trial in DVT treatment (n = 111), an active-controlled trial with enoxaparin sodium in DVT treatment (n = 1,091), and an active-controlled trial with heparin in PE treatment (n = 1,092) (see CLINICAL STUDIES). Hemorrhage: During administration of ARIXTRA, the most common adverse reactions were bleeding complications (see WARNINGS). Hip Fracture, Hip Replacement and Knee Replacement Surgery: The rates of major bleeding events reported during the hip fracture, hip replacement, or knee replacement surgery clinical trials with ARIXTRA 2.5 mg Injection are provided in Tables 8 and 9 below. Table 8. Major Bleeding Episodes 1 in Randomized, Controlled, Hip Fracture, Hip Replacement, and Knee Replacement Surgery Studies Peri-Operative Prophylaxis (Day 1 to Day 7 ± 1 post-surgery) Extended Prophylaxis (Day 8 to Day 28 ± 2 post-surgery) Fondaparinux Sodium Fondaparinux Sodium Indications 2.5 mg SC Enoxaparin Sodium 2, mg SC Placebo SC Hip Fracture 18/831 (2.2%) 19/842 (2.3%) 8/327 (2.4 %) 4 2/329 (0.6 %) Hip Replacement 67/2,268 (3.0%) 55/2,597 (2.1%) Knee Replacement 11/517 (2.1%) 5 1/517 (0.2%) 1 Major bleeding was defined as clinically overt bleeding that was (1) fatal, (2) bleeding at critical site (e.g. intracranial, retroperitoneal, intra-ocular, pericardial, spinal, or into adrenal gland), (3) associated with re-operation at operative site, or (4) with a bleeding index (BI) 2 calculated as [number of whole blood or packed red blood cell units transfused + [(prebleeding) (post-bleeding)] hemoglobin (g/dl) values]. 2 Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg. 3 Not approved for use in patients undergoing hip fracture surgery. 4 During noncomparative, unblinded, peri-operative prophylaxis, major bleeding was reported in 22/737 (3.0%) patients. Fifteen (15) of these 22 patients continued to receive ARIXTRA in extended prophylaxis. After randomization, 4/327 (1.2%) patients experienced major bleeding for the first time. 5 p value versus enoxaparin sodium: <0.01, 95% confidence interval: (1.1%, 3.3%) in group receiving ARIXTRA versus (0.0%, 1.1%) in enoxaparin sodium group. 21

12 Table 9. Bleeding Across Randomized, Controlled Hip Fracture, Hip Replacement and Knee Replacement Surgery Studies Peri-Operative Prophylaxis (Day 1 to Day 7 ± 1 post-surgery) Extended Prophylaxis (Day 8 to Day 28 ± 2 post-surgery) Fondaparinux Sodium Fondaparinux Sodium 2.5 mg SC Enoxaparin Sodium 1, mg SC Placebo SC N = 3,616 N = 3,956 N = 327 N = 329 Major bleeding 3 96 (2.7%) 75 (1.9%) 8 (2.4%) 4 2 (0.6%) Fatal bleeding 0 (0.0%) 1 (<0.1%) 0 (0.0%) 0 (0.0%) Non-fatal 0 (0.0%) 1 (<0.1%) 0 (0.0%) 0 (0.0%) bleeding at critical site Re-operation 12 (0.3%) 10 (0.3%) 2 (0.6%) 2 (0.6%) due to bleeding BI (2.3%) 63 (1.6%) 6 (1.8%) 0 (0.0%) Minor bleeding (3.0%) 116 (2.9%) 5 (1.5%) 2 (0.6%) 1 Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg. 2 Not approved for use in patients undergoing hip fracture surgery. 3 Major bleeding was defined as clinically overt bleeding that was (1) fatal, (2) bleeding at critical site (e.g. intracranial, retroperitoneal, intra-ocular, pericardial, spinal, or into adrenal gland), (3) associated with re-operation at operative site, or (4) with a bleeding index (BI) 2. 4 During non-comparative, unblinded, peri-operative prophylaxis, 2 fatal bleeds were reported (one in a 50 kg patient, one in a severe renal failure patient). 5 BI 2: Overt bleeding associated only with a bleeding index (BI) 2 calculated as [number of whole blood or packed red blood cell units transfused + [(pre-bleeding) (post-bleeding)] hemoglobin (g/dl) values]. 6 Minor bleeding was defined as clinically overt bleeding that was not major. A separate analysis of major bleeding across all randomized, controlled, peri-operative, prophylaxis clinical studies of hip fracture, hip replacement, or knee replacement surgery according to the time of the first injection of ARIXTRA after surgical closure was performed in patients who received ARIXTRA only post-operatively. In this analysis, the incidences of major bleeding were as follows: <4 hours was 4.8% (5/104), 4-6 hours was 2.3% (28/1196), 6-8 hours was 1.9% (38/1965). In all studies, the majority ( 75%) of the major bleeding events occurred during the first 4 days after surgery. Abdominal Surgery: The rates of major bleeding reported during the abdominal surgery clinical trial with ARIXTRA 2.5 mg are provided in Table 10 below. 22

13 Table 10. Major Bleeding Episodes 1 in Randomized, Controlled, Abdominal Surgery Study Fondaparinux Sodium 2.5 mg SC Dalteparin Sodium 5,000 IU SC N = 1,433 N = 1,425 Major bleeding 49 (3.4%) 34 (2.4%) Fatal bleeding 2 (0.1%) 2 (0.1%) Non-fatal bleeding at 0 (0.0%) 0 (0.0%) critical site Other non-fatal major bleeding Surgical site Non-surgical site 38 (2.7%) 9 (0.6%) 26 (1.8%) 6 (0.4%) Minor bleeding 2 31 (2.2%) 23 (1.6%) 1 Major bleeding was defined as bleeding that was (1) fatal, (2) bleeding at the surgical site leading to intervention, (3) non-surgical bleeding at a critical site (e.g. intracranial, retroperitoneal, intra-ocular, pericardial, spinal, or into adrenal gland), or leading to an intervention, and/or with a bleeding index (BI) 2. (BI 2 calculated as [number of whole blood or packed red blood cell units transfused + [(pre-bleeding) (post-bleeding)] hemoglobin (g/dl) values].) 2 Minor bleeding was defined as clinically overt bleeding that was not major. A separate analysis of major bleeding according to the time of the first injection of ARIXTRA after surgical closure was performed. In this analysis the incidences of major bleeding were as follows: <6 hours was 3.4% (9/263) and 6-8 hours was 2.9% (32/1112). Treatment of Deep Vein Thrombosis and Pulmonary Embolism: The rates of bleeding events reported during the DVT and PE clinical trials with the ARIXTRA injection treatment regimen are provided in Table 11 below. 23

14 Table 11. Bleeding 1 in Deep Vein Thrombosis and Pulmonary Embolism Treatment Studies Fondaparinux Sodium Treatment Regimen Enoxaparin Sodium 1 mg/kg SC q 12h Heparin aptt adjusted IV N = 2,294 N = 1,101 N = 1,092 Major bleeding 2 28 (1.2%) 13 (1.2%) 12 (1.1%) Fatal bleeding 3 (0.1%) 0 (0.0%) 1 (0.1%) Non-fatal 3 (0.1%) 0 (0.0%) 2 (0.2%) bleeding at a critical site Intracranial 3 (0.1%) 0 (0.0%) 1 (0.1%) bleeding Retro-peritoneal 0 (0.0%) 0 (0.0%) 1 (0.1%) bleeding Clinically overt 22 (1.0%) 13 (1.2%) 10 (0.9%) bleeding with a 2 g/dl fall in hemoglobin and/or leading to transfusion of PRBC or whole blood 2 units Minor bleeding 3 70 (3.1%) 33 (3.0%) 57 (5.2%) 1 Bleeding rates are during the study drug treatment period (approximately 7 days). Patients were also treated with Vitamin K antagonists initiated within 72 hours after the first study drug administration. 2 Major bleeding was defined as clinically overt: - and/or contributing to death and/or in a critical organ including intracranial, retroperitoneal, intraocular, spinal, pericardial, or adrenal gland and/or associated with a fall in hemoglobin level 2 g/dl and/or leading to a transfusion 2 units of packed red blood cells or whole blood. 3 Minor bleeding was defined as clinically overt bleeding that was not major. Thrombocytopenia: See WARNINGS: Thrombocytopenia. Local Reactions: Mild local irritation (injection site bleeding, rash, and pruritus) may occur following subcutaneous injection of ARIXTRA. Elevations of Serum Aminotransferases: In the peri-operative prophylaxis randomized clinical trials of 7 ± 2 days asymptomatic increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase levels greater than 3 times the upper limit of normal of the laboratory reference range have been reported in 1.7% and 2.6% of patients, respectively, during treatment 24

15 with ARIXTRA 2.5 mg Injection versus 3.2% and 3.9%, of patients, respectively, during treatment with enoxaparin sodium 30 mg every 12 hours or 40 mg enoxaparin sodium. Such elevations are fully reversible and are rarely associated with increases in bilirubin. In the extended prophylaxis clinical trial no significant differences in aspartate (AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase levels between ARIXTRA 2.5 mg Injection and placebo treated patients were observed. In the DVT and PE treatment clinical trials asymptomatic increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase levels greater than 3 times the upper limit of normal of the laboratory reference range have been reported in 0.7% and 1.3% of patients, respectively, during treatment with the ARIXTRA injection treatment regimen. In comparison, these increases have been reported in 4.8% and 12.3%, of patients, respectively, in the DVT treatment trial during treatment with enoxaparin sodium 1 mg/kg every 12 hours, and in 2.9% and 8.7%, of patients, respectively, in the PE treatment trial during treatment with aptt adjusted heparin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like ARIXTRA should be interpreted with caution. Other Adverse Events: Other adverse events that occurred during treatment with ARIXTRA, or enoxaparin sodium in clinical trials with patients undergoing hip fracture surgery, hip replacement surgery, or knee replacement surgery and that occurred at a rate of at least 2% in either treatment group, are provided in Table 12 below. Other adverse events that occurred during treatment with ARIXTRA or dalteparin sodium in clinical trials with patients undergoing abdominal surgery and that occurred at a rate of at least 2% in either treatment group are provided in Table 13 below. Other adverse events that occurred during treatment with ARIXTRA, enoxaparin sodium, or heparin in the DVT and PE treatment clinical trials and that occurred at a rate of at least 2% in any treatment group are provided in Table 14 below. 25

16 Table 12. Adverse Events Occurring in 2% of Patients Treated With ARIXTRA, Enoxaparin Sodium, or Placebo Regardless of Relationship to Study Drug Across Randomized, Controlled, Hip Fracture Surgery, Hip Replacement Surgery, or Knee Replacement Surgery Studies Peri-Operative Prophylaxis Extended Prophylaxis (Day 1 to Day 7 ± 1 post-surgery) (Day 8 to Day 28 ± 2 post-surgery) Fondaparinux Sodium 2.5 mg SC Fondaparinux Sodium 2.5 mg SC Enoxaparin Placebo Adverse Events Sodium 1, 2 SC N = 3,616 N = 3,956 N = 327 N = 329 Anemia 707 (19.6%) 670 (16.9%) 5 (1.5%) 4 (1.2%) Fever 491 (13.6%) 610 (15.4%) 1 (0.3%) 4 (1.2%) Nausea 409 (11.3%) 484 (12.2%) 1 (0.3%) 4 (1.2%) Edema 313 (8.7%) 348 (8.8%) 3 (0.9%) 2 (0.6%) Constipation 309 (8.5%) 416 (10.5%) 6 (1.8%) 7 (2.1%) Rash 273 (7.5%) 329 (8.3%) 2 (0.6%) 4 (1.2%) Vomiting 212 (5.9%) 236 (6.0%) 2 (0.6%) 4 (1.2%) Insomnia 179 (5.0%) 214 (5.4%) 3 (0.9%) 1 (0.3%) Wound drainage 161 (4.5%) 184 (4.7%) 2 (0.6%) 0 (0.0%) increased Hypokalemia 152 (4.2%) 164 (4.1%) 0 (0.0%) 0 (0.0%) Urinary tract 136 (3.8%) 135 (3.4%) 13 (4.0%) 13 (4.0%) infection Dizziness 131 (3.6%) 165 (4.2%) 2 (0.6%) 0 (0.0%) Purpura 128 (3.5%) 137 (3.5%) 0 (0.0%) 0 (0.0%) Hypotension 126 (3.5%) 125 (3.2%) 1 (0.3%) 0 (0.0%) Confusion 113 (3.1%) 132 (3.3%) 4 (1.2%) 1 (0.3%) Bullous 112 (3.1%) 102 (2.6%) 0 (0.0%) 1 (0.3%) eruption 3 Urinary retention 106 (2.9%) 117 (3.0%) 0 (0.0%) 1 (0.3%) Hematoma 103 (2.8%) 109 (2.8%) 7 (2.1%) 1 (0.3%) Diarrhea 90 (2.5%) 102 (2.6%) 6 (1.8%) 8 (2.4%) Dyspepsia 87 (2.4%) 102 (2.6%) 1 (0.3%) 2 (0.6%) Post-operative 85 (2.4%) 69 (1.7%) 2 (0.6%) 2 (0.6%) hemorrhage Headache 72 (2.0%) 97 (2.5%) 0 (0.0%) 2 (0.6%) Pain 62 (1.7%) 101 (2.6%) 0 (0.0%) 0 (0.0%) Surgical site 29 (0.8%) 41 (1.0%) 5 (1.5%) 8 (2.4%) reaction 1 Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg. 2 Not approved for use in patients undergoing hip fracture surgery. 3 Localized blister coded as bullous eruption. 26

17 Table 13: Adverse Events Occurring in 2% of Patients Treated With ARIXTRA or Dalteparin Sodium Undergoing Abdominal Surgery Regardless of Relationship to Study Drug Fondaparinux Sodium 2.5 mg SC Dalteparin Sodium 5000 IU SC Adverse Events N = 1,433 N = 1,425 Post-operative wound infection 70 (4.9%) 69 (4.8%) Post-operative haemorrhage 61 (4.3%) 42 (2.9%) Fever 53 (3.7%) 54 (3.8%) Surgical site reaction 46 (3.2%) 40 (2.8%) Anaemia 35 (2.4%) 26 (1.8%) Hypertension 35 (2.4%) 41 (2.9%) Pneumonia 33 (2.3%) 23 (1.6%) Vomiting 31 (2.2%) 26 (1.8%) Table 14. Adverse Events Occurring in 2% of Patients Treated With ARIXTRA, Enoxaparin Sodium, or Heparin Regardless of Relationship to Study Drug Across VTE Treatment Studies Adverse Events Fondaparinux Sodium Enoxaparin Sodium Heparin N = 2,294 N = 1,101 N = 1,092 Constipation 106 (4.6%) 32 (2.9%) 93 (8.5%) Headache 104 (4.5%) 37 (3.4%) 65 (6.0%) Insomnia 86 (3.7%) 19 (1.7%) 75 (6.9%) Fever 81 (3.5%) 32 (2.9%) 47 (4.3%) Nausea 76 (3.3%) 29 (2.6%) 53 (4.9%) Urinary tract infection 53 (2.3%) 20 (1.8%) 24 (2.2%) Coughing 48 (2.1%) 7 (0.6%) 26 (2.4%) Diarrhea 43 (1.9%) 22 (2.0%) 27 (2.5%) Abdominal pain 33 (1.4%) 14 (1.3%) 28 (2.6%) Chest pain 33 (1.4%) 8 (0.7%) 26 (2.4%) Leg pain 31 (1.4%) 10 (0.9%) 22 (2.0%) Back pain 30 (1.3%) 11 (1.0%) 34 (3.1%) Epistaxis 30 (1.3%) 12 (1.1%) 41 (3.8%) Prothrombin decreased 30 (1.3%) 3 (0.3%) 34 (3.1%) Anemia 28 (1.2%) 3 (0.3%) 23 (2.1%) Vomiting 26 (1.1%) 14 (1.3%) 27 (2.5%) Hypokalemia 25 (1.1%) 2 (0.2%) 23 (2.1%) Bruise 24 (1.0%) 24 (2.2%) 14 (1.3%) Anxiety 18 (0.8%) 8 (0.7%) 22 (2.0%) Hepatic function abnormal 10 (0.4%) 14 (1.3%) 24 (2.2%) Hepatic enzymes increased 7 (0.3%) 52 (4.7%) 30 (2.7%) SGPT increased 7 (0.3%) 47 (4.3%) 8 (0.7%) SGOT increased 4 (0.2%) 31 (2.8%) 3 (0.3%) 27

18 OVERDOSAGE Symptoms/Treatment: There is no known antidote for ARIXTRA Injection. Overdose of ARIXTRA may lead to hemorrhagic complications. Overdosage associated with bleeding complications should lead to treatment discontinuation and initiation of appropriate therapy. Data obtained in patients undergoing chronic intermittent hemodialysis suggest that clearance of ARIXTRA can increase by 20% during hemodialysis. DOSAGE AND ADMINISTRATION ARIXTRA Injection is administered by subcutaneous injection. Deep Vein Thrombosis Prophylaxis Following Hip Fracture, or Hip or Knee Replacement Surgeries: In patients undergoing hip fracture, hip replacement, or knee replacement surgery, the recommended dose of ARIXTRA is 2.5 mg administered by subcutaneous injection. After hemostasis has been established, the initial dose should be given 6 to 8 hours after surgery. Administration before 6 hours after surgery has been associated with an increased risk of major bleeding. The usual duration of administration is 5 to 9 days, and up to 11 days administration has been tolerated. In patients undergoing hip fracture surgery, an extended prophylaxis course of up to 24 additional days is recommended. In patients undergoing hip fracture surgery, a total of 32 days (peri-operative and extended prophylaxis) has been tolerated. (See CLINICAL STUDIES, WARNINGS: Laboratory Testing and ADVERSE REACTIONS.) Deep Vein Thrombosis Prophylaxis Following Abdominal Surgery: In patients undergoing abdominal surgery, the recommended dose of ARIXTRA is 2.5 mg administered by subcutaneous injection after hemostasis has been established. The initial dose should be given 6 to 8 hours after surgery. Administration before 6 hours after surgery has been associated with an increased risk of major bleeding. The usual duration of administration is 5 to 9 days, and up to 10 days of ARIXTRA injection has been administered. Deep Vein Thrombosis and Pulmonary Embolism Treatment: In patients with acute symptomatic DVT and in patients with acute symptomatic PE the recommended dose of ARIXTRA is 5 mg (body weight <50 kg), 7.5 mg (body weight kg), or 10 mg (body weight >100 kg) by subcutaneous injection (ARIXTRA treatment regimen). Treatment with ARIXTRA should be continued for a least 5 days and until a therapeutic oral anticoagulant effect is established (INR 2.0 to 3.0). Concomitant treatment with warfarin sodium should be initiated as soon as possible, usually within 72 hours. The usual duration of administration of ARIXTRA is 5 to 9 days; up to 26 days of ARIXTRA injection has been administered. (See CLINICAL STUDIES, WARNINGS: Laboratory Testing and ADVERSE REACTIONS.) 28

19 INSTRUCTIONS FOR USE Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. ARIXTRA Injection is provided in a single dose, prefilled syringe affixed with an automatic needle protection system. ARIXTRA is administered by subcutaneous injection. It must not be administered by intramuscular injections. ARIXTRA is intended for use under a physician s guidance. Patients may self-inject only if their physician determines that it is appropriate and with medical follow-up as necessary. Proper training in subcutaneous injection technique should be provided. To avoid the loss of drug when using the pre-filled syringe, do not expel the air bubble from the syringe before the injection. Administration should be made in the fatty tissue, alternating injection sites (e.g., between the left and right anterolateral or the left and right posterolateral abdominal wall). To administer ARIXTRA: 1. Wipe the surface of the injection site with an alcohol swab. 2. Twist the plunger cap and remove it (Figure 1). 3. Hold the syringe with either hand and use your other hand to twist the rigid needle guard (covers the needle) counter-clockwise. Pull the rigid needle guard straight off the needle (Figure 2). 29

20 4. Pinch a fold of skin at the injection site between your thumb and forefinger and hold it throughout the injection. 5. Hold the syringe with your thumb on the top pad of the plunger rod and your next 2 fingers on the finger grips on the syringe barrel. Pay attention to avoid sticking yourself with the exposed needle (Figure 3). 6. Insert the full length of the syringe needle perpendicularly into the skin fold held between the thumb and forefinger (Figure 4). 7. Push the plunger rod firmly with your thumb as far as it will go. This will ensure you have injected all the contents of the syringe (Figure 5). 8. When you have injected all the contents of the syringe, the plunger should be released. The plunger will then rise automatically while the needle withdraws from the skin and retracts into the security sleeve. Discard the syringe into the sharps container without replacing the rigid needle guard. 30

21 9. You will know that the syringe has worked when: The needle is pulled back into the security sleeve and the white safety indicator appears above the blue upper body. You may also hear or feel a soft click when the plunger rod is released fully. HOW SUPPLIED ARIXTRA Injection is available in the following strengths and package sizes: 2.5 mg ARIXTRA in 0.5 ml single dose prefilled syringe, affixed with a 27-gauge x ½-inch needle with a blue automatic needle protection system NDC Single Unit Syringes NDC Single Unit Syringes 5 mg ARIXTRA in 0.4 ml single dose prefilled syringe, affixed with a 27-gauge x ½-inch needle with an orange automatic needle protection system NDC Single Unit Syringes NDC Single Unit Syringes 7.5 mg ARIXTRA in 0.6 ml single dose prefilled syringe, affixed with a 27-gauge x ½-inch needle with a magenta automatic needle protection system NDC Single Unit Syringes NDC Single Unit Syringes 10 mg ARIXTRA in 0.8 ml single dose prefilled syringe, affixed with a 27-gauge x ½-inch needle with a violet automatic needle protection system NDC Single Unit Syringes NDC Single Unit Syringes Store at 25 C (77 F); excursions permitted to C (59 86 F) [See USP Controlled Room Temperature]. Keep out of the reach of children. Distributed by GlaxoSmithKline Research Triangle Park, NC ARIXTRA is a registered trademark of GlaxoSmithKline. 2005, GlaxoSmithKline. All rights reserved. October 2005 RL